1 PROJECT SUMMARY/ABSTRACT 2 Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are the major components of 3 chronic lower respiratory disease, the 4th leading cause of death in the United States and the world. Despite 4 this, there are no disease-modifying pharmacologic therapies for COPD. Thus, there are opportunities to 5 advance treatment of COPD by identifying and testing biological therapies that alter disease progression. 6 Candidate: As a pulmonary-critical care-trained physician and Instructor at Brigham and Women's Hospital 7 (BWH) and Harvard Medical School (HMS), the PI has conducted preliminary research identifying platelet 8 activation as a potential risk factor for COPD and emphysema. The PI's long term goal is to become an 9 independent clinical investigator with a focus on strategies that impact the development and progression of 10 emphysema and COPD. Career Development: The PI's short term goals are to complete a Master's Degree in 11 Epidemiology, to learn about imaging analysis, measures of platelet activation and clinical trial design and 12 operations, which she will do with the guidance of the assembled multi-disciplinary mentorship team. 13 Environment: BWH and HMS have a track-record of success in research career development and has 14 committed significant resources to support this proposal including use of the BWH Center for Clinical 15 Investigation. Research: The proposed research aims will evaluate the vascular hypothesis of emphysema and 16 a specific related biological pathway (platelet activation) in sequential steps. Aim 1 will assess the association 17 between pulmonary vascular morphology and the progression of percent emphysema on CT. Aim 2 will 18 measure urinary 11-dehydro-thromboxane B2, a measure of in vivo platelet activation, in a sample of 1,537 19 participants in the Subpopulations and Intermediate Outcomes Measured in COPD Study (SPIROMICS) to test 20 whether platelet activation is associated with emphysema and pulmonary vascular morphology in cross- 21 sectional analyses, and whether it predicts longitudinal progression of emphysema. Aim 3 will recruit 20 novel 22 participants with visual emphysema on CT and mild-moderate COPD for a crossover study to determine 23 whether dual antiplatelet therapy improves pulmonary microvascular perfusion on dual-energy CT scan 24 compared to placebo. Together, these aims link the pulmonary vasculature, platelet activation and emphysema 25 progression, and will test whether inhibiting platelet activation impacts our measures of microvascular 26 pulmonary perfusion. Improvement in pulmonary perfusion with dual antiplatelet therapy would suggest that 27 these therapies may impact long-term progression of emphysema, a hypothesis I would propose to test in a 28 future R01/phase IIb RCT. In completing these research objectives, the PI aims to identify a potential novel 29 pathway related to emphysema and COPD, and gain the expertise to establish an independent research 30 program that identifies and tests therapies that impact the progression of emphysema and COPD.